The present invention relates to modified antibodies bearing glycoside residues that bind to human hepatic asialoglycoprotein receptor, and their use in a method to control the rate of blood clearance of antibodies, which also may be conjugated to therapeutic and/or diagnostic agents.
Antibodies have been used as targeting vehicles for diagnostic and therapeutic agents, e.g. radioisotopes, magnetic resonance imaging (MRI) agents, toxins and cytotoxic drugs, especially in the diagnosis and treatment of cancer and certain infectious diseases. It is often useful to introduce an antibody conjugate, bearing the diagnostic or therapeutic agent, by intravenous injection, but there are instances where such a mode of administration is disadvantageous or where another mode of administration offers particular benefits.
Antibodies alone have also been shown a trigger to cytotoxic effect on cells bearing antigens to which the antibodies bind specifically. This is due to at least two distinct but probably complementary mechanisms, both of which stem from the natural effector functions of antibodies. A first mechanism has been called antibody-dependent cell-mediated cytotoxicity (ADCC), while the other has been called complement-mediated cyctoxicity. Both can be used, either alone or as part of a multi-modal treatment protocol, for therapy of tumors and infectious lesions.
Non-systemic, regional modes of administration of antibodies and antibody conjugates are especially useful in the diagnosis and treatment of tumors and infectious lesions confined within a specific body cavity, e.g., the peritoneal cavity. Intracavitary administration also can obviate the need for a tumor-specific antibody, if the targeting antibody does not bind appreciably to other tissues within the cavity where it is injected prior to passage into the bloodstream. Nevertheless, eventual migration of the antibody conjugate into the bloodstream can result in uptake by normal tissues and can also cause significant damage to bone marrow, in the case of a radiolabeled conjugate. A further problem resulting from uptake into the general circulation is an increase in background radiation, again in the case of a radiolabeled conjugate, due to blood peel activity. The efficacy and safety of certain diagnostic and therapeutic methods using non-systemically administered antibody and antibody fragment conjugates could be enhanced if a method were available for accelerating the rate of rapid clearance of the conjugate once it migrates into the bloodstream.
Conversely, the efficacy of other diagnostic and therapeutic methods using systemically administered antibodies, antibody fragments, or antibody and antibody fragment conjugates could be enhanced if it were possible to manipulate the blood clearance rate of such agents such that little or no clearance occurs for a certain time period, to allow miximum uptake of the agent by the target tissue, followed by rapid clearance of residual circulating agent.
The methods and compositions of the present invention are directed to solving these problems.